Recent investigations demonstrate the importance of receptor for advanced glycation end products (RAGE) mediated signal transduction in promoting pathogenic inflammation, renal failure and diabetic complications. Animal studies indicate that the extracellular domain of RAGE (soluble Rage, sRAGE) can inhibit RAGE function and ameliorate these pathologies, however this form of the protein has unfavorable pharmacokinetics. The overall goal of the present proposal is to further develop an immunoglobulin Fc fusion protein of sRAGE as a novel inhibitor of diabetic complications. The Fc domain is expected to extend the serum half-life of sRAGE which will greatly facilitate its use for chronic disease. In phase I, a series of recombinant, soluble RAGE-Fc fusion proteins was created and the optimal RAGE-Fc construct was selected based on in vitro functional studies as well as simple in vivo models. Phase II will focus on preclinical animal efficacy studies in preparation for an IND. We hypothesize that RAGE-Fc will exhibit superior pharmacokinetics compared to sRAGE (our main competitor for potential RAGE-neutralizing therapeutics). This will be tested directly in Phase II work. Furthermore RAGE-Fc will be compared to sRAGE in three different murine models of diabetic complications: diabetic nephropathy, diabetic atherosclerosis, and diabetic retinopathy. Based on the favorable functional performance of RAGE-Fc as compared to sRAGE in several assays performed during Phase I studies, we expect that RAGE-Fc will also produce results superior to sRAGE in the proposed animal models. PUBLIC HEALTH RELEVANCE: The proposed project will develop a novel therapy for complications of diabetes such as nephropathy, atherosclerosis, and retinopathy.